Pharmaceutical nanoparticles have failed to leverage their unique aerosol drug delivery potential for the treatment of local and systemic diseases due to poor pulmonary deposition efficiency. Because of their submicrometer size, aerosolized nanoparticles can potentially overcome many of the problems associated with traditional inhalation therapy if their lung deposition can be significantly increased. In order to make many next- generation inhaled medications a viable drug delivery alternative, utilizing the full potential of nanoparticles for increased lung delivery and decreased inter- and intra-subject variability are of critical importance. The goal of this project is to address the challenges facing inhaled nanoparticle delivery by developing aerosol formulations that can ensure efficient targeted nanoparticle lung deposition. This concept consists of engineering dry powder nanoparticle aerosols containing a model drug and a hygroscopic excipient. The engineered nanoparticles will be delivered in the size range of 100 - 900 nm in order to minimize mouth- throat deposition and maximize drug payload. After bypassing the upper airways, the natural humidity in the lungs will cause the hygroscopic excipient to accumulate water, increasing the size and weight of the nanoparticles. The increased aerodynamic diameter of the particles will then ensure increased lung deposition rather than exhalation of the aerosol and can potentially be used to target the site of deposition. To achieve this goal, the following specific aims are proposed: Specific Aim 1: Generate and characterize engineered pharmaceutical nanoparticles consisting of drug and a hygroscopic excipient to be used in the excipient enhanced growth (EEG) studies. Specific Aim 2: Evaluate nanoparticle growth in conjunction with upper and lower lung deposition of the engineered aerosol using concurrent CFD modeling and in vitro testing. Specific Aim 3: Evaluate and optimize a dry powder inhaler (DPI) design for nanoparticle dispersion and delivery using a quantitative analysis and design approach. By delivering nanoparticles past the mouth-throat and then increasing their aerosol size through excipient enhanced hygroscopic growth, significant reductions in upper airway deposition are expected. As a result of using this concept, reduced variability in dose can be achieved together with near full lung retention, which are necessary for the effective use of many next-generation pharmaceutical aerosols. PUBLIC HEALTH RELEVANCE: The inhalation of pharmaceutical nanoparticles may offer many unique advantages compared to conventional delivery methods for the treatment of respiratory diseases, systemic conditions and to unlock the potential use of the lungs to deliver vaccines and gene therapy. However, the current methods used to administer these next-generation nanoparticle pharmaceuticals to the lungs are often inefficient, which can significantly reduce drug effectiveness, increase unwanted side effects, and make dosing difficult to control. The overall goal of this project is to develop a novel technology for the efficient delivery of inhaled nanoparticles that minimizes deposition in the mouth and throat while maximizing deposition in the lungs.